U.S. patent number 7,960,561 [Application Number 11/919,708] was granted by the patent office on 2011-06-14 for 2-(phenylamino) benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels.
This patent grant is currently assigned to Neurosearch A/S. Invention is credited to Palle Christophersen, Tina Holm Johansen, Karin Sandager Nielsen, Dan Peters, Ulrik Svane Sorensen, Dorte Strob.ae butted.k, Lene Teuber.
United States Patent |
7,960,561 |
Sorensen , et al. |
June 14, 2011 |
2-(phenylamino) benzimidazole derivatives and their use as
modulators of small-conductance calcium-activated potassium
channels
Abstract
This invention relates to novel 2-(phenylamino)benzimidazole
derivatives useful as modulators of small-conductance
calcium-activated potassium channels (SK channels). In other
aspects the invention relates to the use of these compounds in a
method for therapy and to pharmaceutical compositions comprising
the compounds of the invention.
Inventors: |
Sorensen; Ulrik Svane (Soborg,
DK), Teuber; Lene (V.ae butted.lose, DK),
Peters; Dan (Malmo, DK), Strob.ae butted.k; Dorte
(Farum, DK), Johansen; Tina Holm (Smorum,
DK), Nielsen; Karin Sandager (Fredensborg,
DK), Christophersen; Palle (Ballerup, DK) |
Assignee: |
Neurosearch A/S (Ballerup,
DK)
|
Family
ID: |
37526982 |
Appl.
No.: |
11/919,708 |
Filed: |
June 21, 2006 |
PCT
Filed: |
June 21, 2006 |
PCT No.: |
PCT/EP2006/063405 |
371(c)(1),(2),(4) Date: |
October 31, 2007 |
PCT
Pub. No.: |
WO2006/136580 |
PCT
Pub. Date: |
December 28, 2006 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090076106 A1 |
Mar 19, 2009 |
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Foreign Application Priority Data
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Jun 21, 2005 [DK] |
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2005 00910 |
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Current U.S.
Class: |
548/307.4 |
Current CPC
Class: |
A61P
1/10 (20180101); A61P 1/12 (20180101); A61P
21/02 (20180101); A61P 25/22 (20180101); A61P
35/00 (20180101); A61P 9/10 (20180101); A61P
1/00 (20180101); A61P 1/04 (20180101); A61P
25/00 (20180101); A61P 25/04 (20180101); A61P
37/04 (20180101); A61P 13/12 (20180101); A61P
25/28 (20180101); A61P 25/18 (20180101); A61P
25/08 (20180101); A61P 9/08 (20180101); A61P
25/02 (20180101); C07D 235/30 (20130101); A61P
15/00 (20180101); A61P 9/04 (20180101); A61P
25/16 (20180101); A61P 15/10 (20180101); A61P
29/00 (20180101); A61P 11/00 (20180101); A61P
17/14 (20180101); A61P 25/06 (20180101); A61P
25/24 (20180101); A61P 9/12 (20180101); A61P
15/06 (20180101); A61P 21/00 (20180101); A61P
21/04 (20180101); A61P 43/00 (20180101); A61P
9/00 (20180101); A61P 9/06 (20180101); A61P
1/06 (20180101); A61P 3/10 (20180101); A61P
27/16 (20180101); A61P 13/10 (20180101); A61P
11/06 (20180101); A61P 1/02 (20180101) |
Current International
Class: |
A61K
31/4184 (20060101); C07D 235/30 (20060101) |
Field of
Search: |
;548/307.4 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2430412 |
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Jun 2002 |
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CA |
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1.358.741 |
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Apr 1964 |
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FR |
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1171904 |
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Nov 1969 |
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GB |
|
2-306916 |
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Dec 1990 |
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JP |
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WO-01/21160 |
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Mar 2001 |
|
WO |
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WO-02/46169 |
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Jun 2002 |
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WO |
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WO-2004/069811 |
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Aug 2004 |
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WO |
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WO-2004/098494 |
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Nov 2004 |
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WO |
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WO-2005/044793 |
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May 2005 |
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WO |
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Other References
Sailer et al., "Comparative immunohistochemical distribution of
three small-conductance Ca2.+-.activated potassium channel
subunits, SK1, SK2, and SK3 in mouse brain," Mol. Cell. Neurosci.,
2004, vol. 26, pp. 458-469. cited by other .
Liegeois et al., "Modulation of small conductance calcium-activated
potassium (SK) channels: a new challenge in medicinal chemistry,"
Current Medicinal Chemistry, 2003, vol. 10, pp. 625-647. cited by
other .
Zhu et al., "Studies on fluorine-containing aromatic heterocyclic
compounds. 4. Reactions of 3-trifluoromethylphenyl and
2-chloro-5-trifluoromethylphenyl isocyanide dichlorides with
bifunctional nucleophiles," Journal of Fluorine Chemistry, 1989,
vol. 43, No. 3, pp. 319-327. cited by other .
Caplus Accession No. 2003:959005, Alagarsamy et al., "Antibacterial
activity of some 2-(substituted amino) benzinidazoles," Indian
Pharmacist, 2003, vol. 2, No. 8, pp. 78-79. cited by other .
Grimmett, "Product class 4: benzimidazoles," Science of Synthesis,
2002, vol. 12, pp. 529-612. cited by other .
Claramunt et al., "Aromatic systems with 10 .pi. electrons derived
from 3a-azapentalene. XV. Heterocyclic derivatives from
3a-azapentalene by aryne synthesis," Anales de Quimica, 1975, vol.
71, No. 2, pp. 206-207. cited by other .
Murphy, "Carbonimidoyl dihalides as organic intermediates. I. The
preparation of 2-aryl aminobenzimidazoles," Journal of Organic
Chemistry, 1964, vol. 29, No. 6, pp. 1613-1615. cited by other
.
Caplus Accession No. 1954:5037, Matsui et al., "Mothproofing agents
for wool. XIII. Relation between teh chemical constitution of
mothproofing agents and their effects on wool," J. Soc. Org.
Synthetic Chem., 1952, vol. 10, pp. 333-335. cited by other .
Garin et al., "A facile synthesis of dimethyl
N-aryldithiocarbonimidates and 2-arylaminobenzimidazoles,"
Synthesis, 1983, pp. 375-376. cited by other .
Tuncbilek et al., "Synthesis and antimicrobial activity of some new
anilinobenzimidazoles," Arch. Pharm. Pharm. Med. Chem., 1997, vol.
330, No. 12, pp. 372-376. cited by other .
Caplus Accession No. 2001:732016, Krchnak et al., "Solid-phase
traceless synthesis of selected nitrogen-containing heterocyclic
compounds. The encore technique for directed sorting of modular
solid support," Vollection of Czechoslovak Chemical Communications,
2001, vol. 66, No. 7, pp. 1078-1106. cited by other .
Omelka et al., "EPR study of nitroxyl radicals of substituted
5-anilinotriazoles, 5-anilinotetrazoles, and
2-anilinobenzimidazoles," Collection of Czechoslovak Chemical
Communications, 1992, vol. 57, No. 5, pp. 1065-1071. cited by other
.
Merchan et al., "Synthesis of 2-aryliminoimidazolidines and
2-arylaminobenzimidazoles from methyl n-arylditriocarbamates,"
Synthesis, 1982, pp. 482-484. cited by other .
Omar et al., "The cyclodesulfurization of thio compounds; XVI.
Dicyclohexylbarbodiimide as an efficient cyclodesulfurizing agent
in the synthesis of heterocyclic compounds from various thio
compounds," Synthesis, 1977, pp. 864-865. cited by other .
Krchnak et al., "A solid phase traceless synthesis of
2-arylaminobenzimidazoles," Tetrahedron Letters, 2001, vol. 42, pp.
1627-1630. cited by other .
Jarrott et al., "Characterization of .alpha.-adrenoceptors in rat
and guinea pig tissues using radiolabeled agonists and
antagonists," Circulation Research, 1980, vol. 46, No. 1, pp.
15-20. cited by other .
Caplus Accession No. 1975:541756, Lebedeva et al., "Dependence of
acute toxicity on structure in a series of 2-substituted
benzimidzazoles," Meditsinskaya Parazitologiya i Parazitarnye
Bolezni, 1975, vol. 44, No. 3, pp. 316-322. cited by other .
Jen et al., "Amidines and related compounds. 6. Studies on
structure-activity relationships of antihypertensive and
antisecretory agents related to clonidine," Journal of Medicinal
Chemistry, 1975, vol. 18, No. 1, pp. 90-99. cited by other .
Caplus Accession No. 1990:178787, Kolesnikova et al., "Reaction of
N-pentafluorophenylcarbonimidoyl dichloride with primary aminds,"
Zhurnal Organischeskoi Khimii, 1989, vol. 25, No. 8, pp. 1689-1695.
cited by other .
Wang et al., "A practical synthesis of
2-(N-substituted)-amino-benzimidazoles utilizing CuCI-promoted
intramolecular cyclization of N-(2-aminoaryl)thioureas,"
Tetrahedron Letters, 2004, vol. 45, pp. 7167-7170. cited by
other.
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Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch, LLP
Claims
The invention claimed is:
1. A compound of Formula I: ##STR00005## any of its stereoisomers
or any mixture of its stereoisomers, or a pharmaceutically
acceptable salt thereof; wherein R.sup.1 represents ##STR00006##
wherein either R.sup.b is selected from the group consisting of:
trifluoromethyl and trifluoromethoxy; R.sup.c is selected from the
group consisting of: fluoro and bromo; and R.sup.a and R.sup.d each
represent hydrogen; or R.sup.b is selected from the group
consisting of: halo, trifluoromethyl and trifluoromethoxy; R.sup.d
is selected from the group consisting of: halo, trifluoromethyl and
trifluoromethoxy; and R.sup.a and R.sup.c each represent hydrogen;
and R.sup.2, R.sup.3 and R.sup.4 each represent hydrogen.
2. The compound of claim 1, wherein R.sup.b is selected from the
group consisting of: trifluoromethyl and trifluoromethoxy; R.sup.c
is selected from the group consisting of: fluoro and bromo; and
R.sup.a and R.sup.d each represent hydrogen.
3. The compound of claim 1, wherein R.sup.b is selected from the
group consisting of: halo, trifluoromethyl and trifluoromethoxy;
R.sup.d is selected from the group consisting of: halo,
trifluoromethyl and trifluoromethoxy; and R.sup.a and R.sup.c each
represent hydrogen.
4. The compound of claim 1 or 2, which is
N-(Benzimidazol-2-yl)-4-fluoro-3-(trifluoromethyl)aniline; or
N-(Benzimidazol-2-yl)-4-bromo-3-(trifluoromethyl)aniline; or a
pharmaceutically acceptable salt thereof.
5. The compound of claim 1 or 3, which is
N-(Benzimidazol-2-yl)-3,5-bis(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-3,5-dichloroaniline; or
N-(Benzimidazol-2-yl)-3-fluoro-5-(trifluoromethyl)aniline; or a
pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition, comprising a therapeutically
effective amount of a compound of any one of claims 1-3, or any of
its stereoisomers or any mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, together with at least
one pharmaceutically acceptable carrier, excipient or diluent.
Description
TECHNICAL FIELD
This invention relates to novel 2-(phenylamino)benzimidazole
derivatives useful as modulators of small-conductance
calcium-activated potassium channels (SK channels).
In other aspects the invention relates to the use of these
compounds in a method for therapy and to pharmaceutical
compositions comprising the compounds of the invention.
BACKGROUND ART
Three subtypes of small-conductance calcium-activated potassium
channels (SK channels) have been cloned: SK1, SK2 and SK3
(corresponding to KCNN1-3 using the genomic nomenclature). The
activity of these channels is determined by the concentration of
free intracellular calcium ([Ca.sup.2+].sub.i) via calmodulin that
is constitutively bound to the channels. SK channels are tightly
regulated by [Ca.sup.2+].sub.i in the physiological range being
closed at [Ca.sup.2+].sub.i up to around 0.1 .mu.M but fully
activated at a [Ca.sup.2+].sub.i of 1 .mu.M. Being selective for
potassium, open or active SK channels have a hyperpolarizing
influence on the membrane potential of the cell. SK channels are
widely expressed in the central nervous system. The distribution of
SK1 and SK2 show a high degree of overlap and display the highest
levels of expression in neocortical, limbic and hippocampal areas
in the mouse brain. In contrast, the SK3 channels show high levels
of expression in the basal ganglia, thalamus and the brain stem
monoaminergic neurons e.g. dorsal raphe, locus coeruleus and the
ventral tegmental area (see Sailer et al.: Comparative
immunohistochemical distribution of three small-conductance
Ca.sup.2+-activated potassium channel subunits, SK1, SK2, and SK3
in mouse brain; Mol. Cell. Neurosci. 2004 26 458-469). The SK
channels are also present in several peripheral cells including
skeletal muscle, gland cells, liver cells and T-lymphocytes.
The hyperpolarizing action of active SK channels plays an important
role in the control of firing pattern and excitability of excitable
cells. SK channel inhibitors such as apamin and
bicuculline-methobromide have been demonstrated to increase
excitability whereas the opener 1-EBIO is able to reduce electrical
activity. In non-excitable cells where the amount of Ca.sup.2+
influx via voltage-independent pathways is highly sensitive to the
membrane potential an activation of SK channels will increase the
driving force whereas a blocker of SK channels will have a
depolarising effect and thus diminish the driving force for
calcium.
Based on the important role of SK channels in linking
[Ca.sup.2+].sub.i and membrane potential, SK channels are an
interesting target for developing novel therapeutic agents.
A review of SK channels and SK channel modulators may be found in
Liegeois J-F et al.: Modulation of small conductance
calcium-activated potassium (SK) channels: a new challenge in
medicinal chemistry"; Current Medicinal Chemistry 2003 10
625-647.
Known modulators of SK channels suffer from being large molecules
or peptides (apamin, scyllatoxin, tubocurarine, dequalinium
chloride, UCL1684) or having low potency (1-EBIO, riluzole). Thus,
there is a continued need for compounds with an optimized
pharmacological profile. In particular, there is a great need for
selective ligands, such as SK3 channel modulators.
SUMMARY OF THE INVENTION
In its first aspect, the invention provides a compound of Formula
I:
##STR00001## any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are as defined below.
In its second aspect, the invention provides a pharmaceutical
composition, comprising a therapeutically effective amount of a
compound of the invention, any of its isomers or any mixture of its
isomers, or a pharmaceutically acceptable salt thereof, together
with at least one pharmaceutically acceptable carrier, excipient or
diluent.
In a further aspect, the invention provides the use of a compound
of the invention, any of its isomers or any mixture of its isomers,
or a pharmaceutically acceptable salt thereof, for the manufacture
of a pharmaceutical composition for the treatment, prevention or
alleviation of a disease or a disorder or a condition of a mammal,
including a human, which disease, disorder or condition is
responsive to modulation of SK channels.
In a still further aspect, the invention relates to a method for
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disorder, disease or condition is responsive to modulation of SK
channels, which method comprises the step of administering to such
a living animal body in need thereof a therapeutically effective
amount of a compound of the invention, any of its isomers or any
mixture of its isomers, or a pharmaceutically acceptable salt
thereof.
Other objects of the invention will be apparent to the person
skilled in the art from the following detailed description and
examples.
DETAILED DISCLOSURE OF THE INVENTION
2-(phenylamino)benzimidazole Derivatives
In its first aspect the present invention provides a compound of
Formula I:
##STR00002## any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1
represents a phenyl group; which phenyl group is substituted with
one or more substituents independently selected from the group
consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano,
alkyl, alkoxy and phenyl; R.sup.2 represents hydrogen or alkyl;
R.sup.3 and R.sup.4 independent of each other are selected from the
group consisting of: hydrogen, halo, trifluoromethyl,
trifluoromethoxy, cyano, --NR'R'', alkyl and alkoxy wherein R' and
R'' independent of each other are hydrogen or alkyl;
with the proviso that the compound is not
N-Benzimidazol-2-yl)-aniline, N-Benzimidazol-2-yl)-4-chloroaniline,
N-Benzimidazol-2-yl)-4-fluoroaniline,
N-Benzimidazol-2-yl)-3-chloro-aniline,
N-Benzimidazol-2-yl)-3-trifluoromethyl-aniline, or
N-Benzimidazol-2-yl)-4-chloro-3-trifluoromethyl-aniline.
In one embodiment, R.sup.1 represents
##STR00003## wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d
independent of each other are selected from the group consisting
of:
hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl,
alkoxy and phenyl; with the proviso that not all four of R.sup.a,
R.sup.b, R.sup.c and R.sup.d represent hydrogen.
In a more preferred embodiment R.sup.a, R.sup.b, R.sup.c and
R.sup.d independent of each other are selected from the group
consisting of hydrogen, halo, trifluoromethyl, trifluoromethoxy,
cyano and alkyl; with the proviso that not all four of R.sup.a,
R.sup.b, R.sup.c and R.sup.d represent hydrogen.
In a second embodiment, R.sup.a and R.sup.b independent of each
other are selected from the group consisting of: halo,
trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy and phenyl;
and R.sup.c and R.sup.d represent hydrogen. In a special
embodiment, R.sup.a represents alkyl, such as methyl, and R.sup.b
represents trifluoromethyl. In a further embodiment, R.sup.a
represents halo, such as fluoro, and R.sup.b represents
trifluoromethyl.
In a more preferred embodiment, R.sup.a and R.sup.b independent of
each other are selected from the group consisting of halo,
trifluoromethyl, trifluoromethoxy, cyano, and alkyl; and R.sup.c
and R.sup.d represent hydrogen.
In a further embodiment, R.sup.b and R.sup.c independent of each
other are selected from the group consisting of: halo,
trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy and phenyl;
and R.sup.a and R.sup.d represent hydrogen. In a special
embodiment, R.sup.b represents halo, such as chloro or fluoro, and
R.sup.c represents halo, such as chloro or fluoro. In a further
embodiment, R.sup.b represents trifluoromethyl and R.sup.c
represents halo, such as chloro, fluoro or bromo. In a still
further embodiment, R.sup.b represents alkyl, such as methyl, and
R.sup.c represents halo, such as fluoro. In a further embodiment,
R.sup.b represents trifluoromethyl and R.sup.c represents alkyl,
such as methyl.
In a more preferred embodiment, R.sup.b and R.sup.c independent of
each other are selected from the group consisting of halo,
trifluoromethyl, trifluoromethoxy, cyano and alkyl; and R.sup.a and
R.sup.d represent hydrogen.
In a still further embodiment, R.sup.b and R.sup.d independent of
each other are selected from the group consisting of: halo,
trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy and phenyl;
and R.sup.a and R.sup.c represent hydrogen. In a special
embodiment, R.sup.b represents halo, such as chloro or fluoro, and
R.sup.d represents halo, such as chloro or fluoro. In a further
embodiment, R.sup.b represents trifluoromethyl and R.sup.d
represents trifluoromethyl. In a still further embodiment, R.sup.b
represents trifluoromethyl and R.sup.d represents halo, such as
fluoro.
In a more preferred embodiment, R.sup.b and R.sup.d independent of
each other are selected from the group consisting of halo,
trifluoromethyl, trifluoromethoxy, cyano and alkyl; and R.sup.a and
R.sup.c represent hydrogen.
In a further embodiment, R.sup.a, R.sup.b and R.sup.c independent
of each other are selected from the group consisting of: halo,
trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy and phenyl;
and R.sup.d represents hydrogen. In a special embodiment, R.sup.a
represents halo, such as fluoro, R.sup.b represents halo, such as
fluoro, and R.sup.c represents halo, such as fluoro.
In a more preferred embodiment, R.sup.a, R.sup.b and R.sup.c
independent of each other are selected from the group consisting of
halo, trifluoromethyl, trifluoromethoxy, cyano and alkyl; and
R.sup.d represents hydrogen.
In a still further embodiment, one of R.sup.a, R.sup.b and R.sup.c
is selected from the group consisting of: halo, trifluoromethyl,
trifluoromethoxy, cyano, alkyl, alkoxy and phenyl; and R.sup.d and
the remaining two of R.sup.a, R.sup.b and R.sup.c represent
hydrogen. In a special embodiment, R.sup.c represents halo, such as
chloro or fluoro. In a further embodiment, R.sup.c represents
trifluoromethyl. In a still further embodiment, R.sup.c represents
trifluoromethoxy. In a further embodiment, R.sup.b represents halo,
such as chloro. In a still further embodiment, R.sup.b represents
trifluoromethyl.
In a more preferred embodiment, one of R.sup.a, R.sup.b and R.sup.c
is selected from the group consisting of halo, trifluoromethyl,
trifluoromethoxy, cyano and alkyl; and R.sup.d and the remaining
two of R.sup.a, R.sup.b and R.sup.c represent hydrogen.
In a further embodiment, R.sup.2 represents hydrogen.
In a still further embodiment, R.sup.2 represents alkyl, such as
methyl.
In a further embodiment, R.sup.3 and R.sup.4 represent
hydrogen.
In a special embodiment the chemical compound of the invention is
N-(Benzimidazol-2-yl)-4-chloroaniline;
N-(Benzimidazol-2-yl)-4-chloro-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-3,4-dichloroaniline;
N-(Benzimidazol-2-yl)-4-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-3-chloroaniline;
N-(Benzimidazol-2-yl)-4-(trifluoromethoxy)aniline;
N-(Benzimidazol-2-yl)-4-fluoroaniline;
N-(Benzimidazol-2-yl)-3,4-difluoroaniline;
N-(Benzimidazol-2-yl)-3,5-difluoroaniline;
N-(Benzimidazol-2-yl)-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-4-fluoro-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-4-fluoro-3-methylaniline;
N-(Benzimidazol-2-yl)-3,5-bis(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-3-chloro-4-fluoroaniline;
N-(Benzimidazol-2-yl)-3,5-dichloroaniline;
N-(Benzimidazol-2-yl)-4-bromo-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-4-methyl-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-3-fluoro-5-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-2-methyl-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-2-fluoro-3-(trifluoromethyl)aniline;
N-(Benzimidazol-2-yl)-2,3,4-trifluoroaniline;
N-(Benzoimidazol-2-yl)-N-methyl-3,4-dichloroaniline;
N-(Benzoimidazol-2-yl)-3-cyano-aniline;
N-(Benzoimidazol-2-yl)-3-methoxy-5-(trifluoromethyl)aniline;
N-(Benzoimidazol-2-yl)-4-isopropyl-aniline;
N-(Benzoimidazol-2-yl)-2-chloro-5-(trifluoromethyl)aniline;
N-(Benzoimidazol-2-yl)-2-methyl-5-(trifluoromethyl)aniline; or
N-(Benzoimidazol-2-yl)-2-phenyl-aniline;
or a pharmaceutically acceptable salt thereof.
Any combination of two or more of the embodiments as described
above is considered within the scope of the present invention.
Definition of Substituents
In the context of this invention halo represents fluoro, chloro,
bromo or iodo.
In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contains of from one to six carbon
atoms (C.sub.1-6-alkyl), including pentyl, isopentyl, neopentyl,
tertiary pentyl, hexyl and isohexyl. In a preferred embodiment
alkyl represents a C.sub.1-4-alkyl group, including butyl,
isobutyl, secondary butyl, and tertiary butyl. In another preferred
embodiment of this invention alkyl represents a C.sub.1-3-alkyl
group, which may in particular be methyl, ethyl, propyl or
isopropyl.
Alkoxy is O-alkyl, wherein alkyl is as defined above.
Pharmaceutically Acceptable Salts
The chemical compound of the invention may be provided in any form
suitable for the intended administration. Suitable forms include
pharmaceutically (i.e. physiologically) acceptable salts, and pre-
or prodrug forms of the chemical compound of the invention.
Examples of pharmaceutically acceptable addition salts include,
without limitation, the non-toxic inorganic and organic acid
addition salts such as the hydrochloride, the hydrobromide, the
nitrate, the perchlorate, the phosphate, the sulphate, the formate,
the acetate, the aconate, the ascorbate, the benzenesulphonate, the
benzoate, the cinnamate, the citrate, the embonate, the enantate,
the fumarate, the glutamate, the glycolate, the lactate, the
maleate, the malonate, the mandelate, the methanesulphonate, the
naphthalene-2-sulphonate derived, the phthalate, the salicylate,
the sorbate, the stearate, the succinate, the tartrate, the
toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
Examples of pharmaceutically acceptable cationic salts of a
chemical compound of the invention include, without limitation, the
sodium, the potassium, the calcium, the magnesium, the zinc, the
aluminium, the lithium, the choline, the lysine, and the ammonium
salt, and the like, of a chemical compound of the invention
containing an anionic group. Such cationic salts may be formed by
procedures well known and described in the art.
In the context of this invention the "onium salts" of N-containing
compounds are also contemplated as pharmaceutically acceptable
salts. Preferred "onium salts" include the alkyl-onium salts, the
cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
Examples of pre- or prodrug forms of the chemical compound of the
invention include examples of suitable prodrugs of the substances
according to the invention include compounds modified at one or
more reactive or derivatizable groups of the parent compound. Of
particular interest are compounds modified at a carboxyl group, a
hydroxyl group, or an amino group. Examples of suitable derivatives
are esters or amides.
The chemical compound of the invention may be provided in
dissoluble or indissoluble forms together with a pharmaceutically
acceptable solvent such as water, ethanol, and the like. Dissoluble
forms may also include hydrated forms such as the monohydrate, the
dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and
the like. In general, the dissoluble forms are considered
equivalent to indissoluble forms for the purposes of this
invention.
Steric Isomers
It will be appreciated by those skilled in the art that the
compounds of the present invention may contain one or more chiral
centers, and that such compounds exist in the form of isomers.
Moreover, the chemical compounds of the present invention may exist
as enantiomers in (+) and (-) forms as well as in racemic forms
(.+-.). The racemates of these isomers and the individual isomers
themselves are within the scope of the present invention.
The invention includes all such isomers and any mixtures thereof
including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known
methods and techniques. One way of separating the isomeric salts is
by use of an optically active acid, and liberating the optically
active amine compound by treatment with a base. Another method for
resolving racemates into the optical antipodes is based upon
chromatography on an optical active matrix. Racemic compounds of
the present invention can thus be resolved into their optical
antipodes, e.g., by fractional crystallisation of d- or
l-(tartrates, mandelates, or camphorsulphonate) salts for
example.
The chemical compounds of the present invention may also be
resolved by the formation of diastereomeric amides by reaction of
the chemical compounds of the present invention with an optically
active activated carboxylic acid such as that derived from (+) or
(-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic
acid or by the formation of diastereomeric carbamates by reaction
of the chemical compound of the present invention with an optically
active chloroformate or the like.
Additional methods for the resolving the optical isomers are known
in the art. Such methods include those described by Jaques J,
Collet A, & Wilen S in "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, New York (1981).
Optical active compounds can also be prepared from optical active
starting materials.
Labelled Compounds
The compounds of the invention may be used in their labelled or
unlabelled form. In the context of this invention the labelled
compound has one or more atoms replaced by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature. The labelling will allow easy quantitative
detection of said compound.
The labelled compounds of the invention may be useful as diagnostic
tools, radio tracers, or monitoring agents in various diagnostic
methods, and for in vivo receptor imaging.
The labelled isomer of the invention preferably contains at least
one radio-nuclide as a label. Positron emitting radionuclides are
all candidates for usage. In the context of this invention the
radionuclide is preferably selected from .sup.2H (deuterium),
.sup.3H (tritium), .sup.13C, .sup.14C, .sup.131I, .sup.125I,
.sup.123I, and .sup.18F.
The physical method for detecting the labelled isomer of the
present invention may be selected from Position Emission Tomography
(PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic
Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and
Computed Axial X-ray Tomography (CAT), or combinations thereof.
Methods of Preparation
The chemical compounds of the invention may be prepared by
conventional methods for chemical synthesis, e.g. those described
in the working examples. The starting materials for the processes
described in the present application are known or may readily be
prepared by conventional methods from commercially available
chemicals.
Also one compound of the invention can be converted to another
compound of the invention using conventional methods.
The end products of the reactions described herein may be isolated
by conventional techniques, e.g. by extraction, crystallisation,
distillation, chromatography, etc.
Biological Activity
Compounds of the invention may be tested for their ability to
modulate SK channels in vitro. Functional modulation can be
determined by measuring the compound-induced change in SK current
by the patch clamp technique as described by Strob.ae butted.k et
al.: Pharmacological characterization of small-conductance
Ca.sup.2+-activated K channels expressed in HEK293 cells; British
Journal of Pharmacology 2000 129 991-999. From this type of
measurements the potency of a given compound can be determined as
e.g. K.sub.i or IC.sub.50 values for blockers/inhibitors and
EC.sub.50 values for openers/activators. Similar data can be
obtained from other patch clamp configurations and from channels
expressed endogenously in various cell lines.
In one embodiment, the compounds of the invention show selectivity
for SK3 over SK1 and SK2. In a further embodiment, the compounds of
the invention are positive SK channel modulators, such as positive
SK3 channel modulators. In a still further embodiment, the
compounds of the invention are negative modulators, such as
negative SK3 channel modulators. In a special embodiment, the
compounds of the invention are SK channel blockers, such as SK3
channel blockers.
Based on the activity observed in the patch clamp experiments, the
compound of the invention is considered useful for the treatment,
prevention or alleviation of a disease or a disorder or a condition
of a mammal, including a human, which disease, disorder or
condition is responsive to modulation of SK channels.
In a special embodiment, the compounds of the invention are
considered useful for the treatment, prevention or alleviation of:
absence seizures, agerelated memory loss, Alzheimer's disease,
angina pectoris, arrhythmia, asthma, anxiety, ataxia, attention
deficits, baldness, bipolar disorder, bladder hyperexcitability,
bladder outflow obstruction, bladder spasms, brain tumors, cerebral
ischaemia, chronic obstructive pulmonary disease, cancer,
cardiovascular disorders, cognitive dysfunction, colitis,
constipation, convulsions, coronary artery spasms, coronary hearth
disease, cystic fibrosis, dementia, depression, diabetes type II,
dysmenorrhoea, epilepsy, gastrointestinal dysfunction,
gastroesophageal reflux disorder, gastrointestinal hypomotility
disorders gastrointestinal motility insufficiency, hearing loss,
hyperinsulinemia, hypertension, immune suppression, inflammatory
bowel disease, inflammatory pain, intermittent claudication,
irritable bowel syndrome, ischaemia, ischaemic hearth disease,
learning deficiencies, male erectile dysfunction, manic depression,
memory deficits, migraine, mood disorders, motor neuron diseases,
myokymia, myotonic dystrophy, myotonic muscle dystrophia,
narcolepsy, neuropathic pain, pain, Parkinson's disease, polycystic
kidney disease, postoperative ileus, premature labour, psychosis,
psychotic disorders, renal disorders, Reynaud's disease,
rhinorrhoea, secretory diarrhoea, seizures, Sjorgren's syndrome,
sleep apnea, spasticity, sleeping disorders, stroke, traumatic
brain injury, trigeminal neuralgia, urinary incontinence,
urinogenital disorders, vascular spasms, vision loss, and
xerostomia.
It is at present contemplated that a suitable dosage of the active
pharmaceutical ingredient (API) is within the range of from about
0.1 to about 1000 mg API per day, more preferred of from about 10
to about 500 mg API per day, most preferred of from about 30 to
about 100 mg API per day, dependent, however, upon the exact mode
of administration, the form in which it is administered, the
indication considered, the subject and in particular the body
weight of the subject involved, and further the preference and
experience of the physician or veterinarian in charge.
Preferred compounds of the invention show a biological activity in
the sub-micromolar and micromolar range, i.e. of from below 1 to
about 100 .mu.M.
Pharmaceutical Compositions
In another aspect the invention provides novel pharmaceutical
compositions comprising a therapeutically effective amount of the
chemical compound of the invention.
While a chemical compound of the invention for use in therapy may
be administered in the form of the raw chemical compound, it is
preferred to introduce the active ingredient, optionally in the
form of a physiologically acceptable salt, in a pharmaceutical
composition together with one or more adjuvants, excipients,
carriers, buffers, diluents, and/or other customary pharmaceutical
auxiliaries.
In a preferred embodiment, the invention provides pharmaceutical
compositions comprising the chemical compound of the invention, or
a pharmaceutically acceptable salt or derivative thereof, together
with one or more pharmaceutically acceptable carriers, and,
optionally, other therapeutic and/or prophylactic ingredients,
known and used in the art. The carrier(s) must be "acceptable" in
the sense of being compatible with the other ingredients of the
formulation and not harmful to the recipient thereof.
The pharmaceutical composition of the invention may be administered
by any convenient route, which suits the desired therapy. Preferred
routes of administration include oral administration, in particular
in tablet, in capsule, in drage, in powder, or in liquid form, and
parenteral administration, in particular cutaneous, subcutaneous,
intramuscular, or intravenous injection. The pharmaceutical
composition of the invention can be prepared by any skilled person
by use of standard methods and conventional techniques appropriate
to the desired formulation. When desired, compositions adapted to
give sustained release of the active ingredient may be
employed.
Further details on techniques for formulation and administration
may be found in the latest edition of Remington's Pharmaceutical
Sciences (Maack Publishing Co., Easton, Pa.).
The actual dosage depend on the nature and severity of the disease
being treated, and is within the discretion of the physician, and
may be varied by titration of the dosage to the particular
circumstances of this invention to produce the desired therapeutic
effect. However, it is presently contemplated that pharmaceutical
compositions containing of from about 0.1 to about 500 mg of active
ingredient per individual dose, preferably of from about 1 to about
100 mg, most preferred of from about 1 to about 10 mg, are suitable
for therapeutic treatments.
The active ingredient may be administered in one or several doses
per day. A satisfactory result can, in certain instances, be
obtained at a dosage as low as 0.1 .mu.g/kg i.v. and 1 .mu.g/kg
p.o. The upper limit of the dosage range is presently considered to
be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from
about 0.1 .mu.g/kg to about 10 mg/kg/day i.v., and from about 1
.mu.g/kg to about 100 mg/kg/day p.o.
Methods of Therapy
In another aspect the invention provides a method for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disease, disorder or condition is responsive to modulation of SK
channels, and which method comprises administering to such a living
animal body, including a human, in need thereof an effective amount
of a chemical compound of the invention.
It is at present contemplated that suitable dosage ranges are 0.1
to 1000 milligrams daily, 10-500 milligrams daily, and especially
30-100 milligrams daily, dependent as usual upon the exact mode of
administration, form in which administered, the indication toward
which the administration is directed, the subject involved and the
body weight of the subject involved, and further the preference and
experience of the physician or veterinarian in charge.
EXAMPLES
The invention is further illustrated with reference to the
following examples, which are not intended to be in any way
limiting to the scope of the invention as claimed.
General: The procedures represent generic procedures used to
prepare compounds of the invention. Abbreviations used are as
follows:
Me: methyl mp: melting point MW: microwave rt: room temperature
Procedure A
2-Chlorobenzimidazole and the required amine were suspended in
acetonitrile in a closed vial and heated to 150-200.degree. C. for
15-45 min by use of microwave (MW) irradiation. After cooling to rt
the precipitated solid was filtered off and washed with
acetonitrile to give the desired product as a HCl salt.
Alternatively, the precipitate was filtered off and recrystallised
from a mixture of CH.sub.3CN/MeOH or purified by column
chromatography or preparative LCMS to give the desired product as
the free base.
An example of Procedure A, the preparation of
N-(benzimidazol-2-yl)-4-chloro-3-(trifluoromethyl)aniline, is shown
in Scheme 1.
##STR00004##
Example 1
N-(Benzimidazol-2-yl)-4-chloroaniline
The title compound was prepared from 2-chlorobenzimidazole and
4-chloroaniline by Procedure A. The product was isolated by
filtration and recrystallisation to give the title compound as a
hydrochloride salt (white solid, mp 238-240.degree. C.).
MS(ES.sup.+) m/z 244 ([M+1].sup.+, 100).
Example 2
N-(Benzimidazol-2-yl)-4-chloro-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
4-chloro-3-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration and recrystallisation to give the title
compound as a hydrochloride salt (white solid, mp 255-260.degree.
C.). MS(ES.sup.+) m/z 312 ([M+1].sup.+, 100).
Example 3
N-(Benzimidazol-2-yl)-3,4-dichloroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3,4-dichloroaniline by Procedure A. The product was isolated by
filtration to give the title compound as a hydrochloride salt
(white solid, mp>270.degree. C.). MS(ES.sup.+) m/z 278 (M.sup.+,
100).
Example 4
N-(Benzimidazol-2-yl)-4-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
4-(trifluoromethyl)aniline by Procedure A. The product was isolated
by filtration and preparative LCMS to give the title compound as
the free base (white solid, mp 199-200.degree. C.). MS(ES.sup.+)
m/z 278 ([M+1].sup.+, 100).
Example 5
N-(Benzimidazol-2-yl)-3-chloroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3-chloroaniline by Procedure A. The product was isolated by
filtration to give the title compound as a hydrochloride salt
(white solid, mp 252-257.degree. C.). MS(ES.sup.+) m/z 244
([M+1].sup.+, 100).
Example 6
N-(Benzimidazol-2-yl)-4-(trifluoromethoxy)aniline
The title compound was prepared from 2-chlorobenzimidazole and
4-(trifluoromethoxy)aniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp 250-251.degree. C.).
MS(ES.sup.+) m/z 294 ([M+1].sup.+, 100).
Example 7
N-(Benzimidazol-2-yl)-4-fluoroaniline
The title compound was prepared from 2-chlorobenzimidazole and
4-fluoroaniline by Procedure A. The product was isolated by
filtration to give the title compound as a hydrochloride salt
(solid, mp 215-216.degree. C.). MS(ES.sup.+) m/z 228 ([M+1].sup.+,
100).
Example 8
N-(Benzimidazol-2-yl)-3,4-difluoroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3,4-difluoroaniline by Procedure A. The product was isolated by
filtration to give the title compound as a hydrochloride salt
(white solid, mp 283-284.degree. C.). MS(ES.sup.+) m/z 246
([M+1].sup.+, 100).
Example 9
N-(Benzimidazol-2-yl)-3,5-difluoroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3,5-difluoroaniline by Procedure A. The product was isolated by
filtration to give the title compound as a hydrochloride salt
(white solid, mp 292-293.degree. C.). MS(ES.sup.+) m/z 246
([M+1].sup.+, 100).
Example 10
N-(Benzimidazol-2-yl)-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
3-(trifluoromethyl)aniline by Procedure A. The product was isolated
by filtration and preparative LCMS to give the title compound as
the free base (white solid, mp 160-162.degree. C.). MS(ES.sup.+)
m/z 278 ([M+1].sup.+, 100).
Example 11
N-(Benzimidazol-2-yl)-4-fluoro-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
4-fluoro-3-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp 255-257.degree. C.).
MS(ES.sup.+) m/z 296 ([M+1].sup.+, 100).
Example 12
N-(Benzimidazol-2-yl)-4-fluoro-3-methylaniline
The title compound was prepared from 2-chlorobenzimidazole and
4-fluoro-3-methylaniline by Procedure A. The product was isolated
by filtration to give the title compound as a hydrochloride salt
(solid, mp 246-248.degree. C.). MS(ES.sup.+) m/z 242 ([M+1].sup.+,
100).
Example 13
N-(Benzimidazol-2-yl)-3,5-bis(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
3,5-bis(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp 245-246.degree. C.).
MS(ES.sup.+) m/z 346 ([M+1].sup.+, 100).
Example 14
N-(Benzimidazol-2-yl)-3-chloro-4-fluoroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3-chloro-4-fluoroaniline by Procedure A. The product was isolated
by filtration to give the title compound as a hydrochloride salt
(white solid, mp 306-307.degree. C.). MS(ES.sup.+) m/z 262
([M+1].sup.+, 100).
Example 15
N-(Benzimidazol-2-yl)-3,5-dichloroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3,5-dichloroaniline by Procedure A. The product was isolated by
filtration to give the title compound as a hydrochloride salt
(solid, mp 317-318.degree. C.). MS(ES.sup.+) m/z 278 (M.sup.+,
100).
Example 16
N-(Benzimidazol-2-yl)-4-bromo-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
4-bromo-3-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp 262-264.degree. C.).
MS(ES.sup.+) m/z 356 (M.sup.+, 100).
Example 17
N-(Benzimidazol-2-yl)-4-methyl-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
4-methyl-3-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp>265.degree. C.).
MS(ES.sup.+) m/z 292 ([M+1].sup.+, 100).
Example 18
N-(Benzimidazol-2-yl)-3-fluoro-5-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
3-fluoro-5-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp 263-265.degree. C.).
MS(ES.sup.+) m/z 296 ([M+1].sup.+, 100).
Example 19
N-(Benzimidazol-2-yl)-2-methyl-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
2-methyl-3-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration and preparative LCMS to give the title
compound as the free base (white solid, mp 204-206.degree. C.).
MS(ES.sup.+) m/z 292 ([M+1].sup.+, 100).
Example 20
N-(Benzimidazol-2-yl)-2-fluoro-3-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
2-fluoro-3-(trifluoromethyl)aniline by Procedure A. The product was
isolated by filtration and preparative LCMS to give the title
compound as the free base (solid, mp 91-92.degree. C.).
MS(ES.sup.+) m/z 296 ([M+1].sup.+, 100).
Example 21
N-(Benzimidazol-2-yl)-2,3,4-trifluoroaniline
The title compound was prepared from 2-chlorobenzimidazole and
2,3,4-trifluoroaniline by Procedure A. The product was isolated by
filtration and preparative LCMS to give the title compound as the
free base (white solid, mp 182-183.degree. C.). MS(ES.sup.+) m/z
264 ([M+1].sup.+, 100).
Example 22
N-(Benzoimidazol-2-yl)-N-methyl-3,4-dichloroaniline
The title compound was prepared from 2-chlorobenzimidazole and
3,4-dichhloro-N-methylaniline by Procedure A. The product was
isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp>275.degree. C.).
MS(ES.sup.+) m/z 292 (M.sup.+, 100).
Example 23
N-(Benzoimidazol-2-yl)-3-cyanoaniline
The title compound was prepared from 2-chlorobenzimidazole and
3-aminobenzonitrile by Procedure A. The product was isolated by
filtration and preparative LCMS to give the title compound as the
free base (white solid, mp 272-274.degree. C.). MS(ES.sup.+) m/z
235 ([M+1].sup.+, 100).
Example 24
N-(Benzoimidazol-2-yl)-3-methoxy-5-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
3-methoxy-5-(trifluoromethyl)aniline by Procedure A. The product
was isolated by filtration to give the title compound as a
hydrochloride salt (white solid, mp 212-213.degree. C.).
MS(ES.sup.+) m/z 308 ([M+1].sup.+, 100).
Example 25
N-(Benzoimidazol-2-yl)-4-isopropylaniline
The title compound was prepared from 2-chlorobenzimidazole and
4-isopropylaniline by Procedure A. The product was isolated upon
basic work-up and recrystallized from acetonitrile to give the
title compound as the free base (white solid, mp 179-180.degree.
C.). MS(ES.sup.+) m/z 252 ([M+1].sup.+, 100).
Example 26
N-(Benzoimidazol-2-yl)-2-chloro-5-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
3-amino-4-chlorobenzotrifluoride by Procedure A. The product was
isolated upon basic work-up and purified by preparative LCMS to
give the title compound as the free base. .sup.1NMR (CDCl.sub.3)
.delta. 6.40 (br s, 2H), 7.11-7.15 (d, 1H), 7.18-7.25 (m, 2H),
7.35-7.41 (d, 1H), 7.42-7.46 (m, 2H), 8.57 (s, 1H). MS(ES.sup.+)
m/z 312 ([M+1].sup.+, 100).
Example 27
N-(Benzoimidazol-2-yl)-2-methyl-5-(trifluoromethyl)aniline
The title compound was prepared from 2-chlorobenzimidazole and
3-amino-4-methylbenzotrifluoride by Procedure A. The product was
isolated upon basic work-up and purified by preparative LCMS to
give the title compound as the free base. .sup.1NMR (DMSO-d6)
.delta. 2.40 (s, 3H), 6.95-7.03 (m, 2H), 7.20-7.25 (m, 1H),
7.31-7.42 (m, 3H), 8.63 (s, 1H), 8.88 (s, 1H), 10.9 (s, 1H).
MS(ES.sup.+) m/z 292 ([M+1].sup.+, 100).
Example 28
N-(Benzoimidazol-2-yl)-2-phenylaniline
The title compound was prepared from 2-chlorobenzimidazole and
2-amino-biphenyl by Procedure A. The crude product was purified by
preparative LCMS to give the title compound as the free base (white
solid, mp 152-154.degree. C.). MS(ES.sup.+) m/z 286 ([M+1].sup.+,
100).
* * * * *